Absence of Vasoactive Intestinal Peptide Expression in Hematopoietic Cells Enhances Th1 Polarization and Antiviral Immunity in Mice

Abstract

Vasoactive intestinal peptide (VIP) induces regulatory dendritic cells (DC) in vitro that inhibit cellular immune responses. We tested the role of physiological levels of VIP on immune responses to murine cytomegalovirus (mCMV) using VIP-knockout (VIP-KO) mice and radiation chimeras engrafted with syngenic VIP-KO hematopoietic cells. VIP-KO mice and had less weight loss and better survival following mCMV infection compared with wild-type littermates (WT). MCMV-infected VIP-KO mice had lower viral loads, faster clearance of virus, with increased numbers of IFN-γ+ NK and NKT cells, and enhanced cytolytic activity of NK cells. Adaptive anti-viral cellular immunity was increased in mCMV-infected VIP-KO mice compared with WT mice, with more Th1/Tc1 polarized T-cells, fewer IL-10+ T-cells, and more mCMV-M45 epitope peptide-MHC class I-tetramer+ CD8+ T-cells (tetramer+ CD8 T-cells). MCMV-immune VIP-KO mice had enhanced ability to clear mCMV-peptide pulsed target cells in vivo. Enhanced anti-viral immunity was also seen in WT transplant recipients engrafted with VIP-KO hematopoietic cells, indicating that VIP synthesized by neuronal cells did not suppress immune responses. Following mCMV infection there was a marked up-regulation of MHC class II (MHC-II) and CD80 co-stimulatory molecule expression on DC from VIP-KO mice compared with DC from WT mice, while PD-1 and PD-L1 expression were up-regulated in activated CD8+ T-cells and DC, respectively, in WT mice but not in VIP-KO mice. Since the absence of VIP in immune cells increased innate and adaptive anti-viral immunity by altering co-stimulatory and co-inhibitory pathways, selective targeting of VIP-signaling represents an attractive therapeutic target to enhance anti-viral immunity.

Pharmacological inhibition of VIP signaling enhances antiviral immunity and improves survival in murine cytomegalovirus-infected allogeneic bone marrow transplant recipients

“…Preparation of BM cells and splenocytes from VIP-KO or WT B6 mice, and irradiation (11Gy) of CB6/F1 and B10BR recipient mice were performed as previously described. 8,12,13 On day 0, irradiated mice received 5 3 10 6 T-cell depleted BM (TCD-BM) cells with 0, 1 3 10 6 , 3 3 10 6 , or 8 3 10 6 donor splenocytes or 0.1 3 10 6 , 0.3 3 10 6 , or 1 3 10 6 purified donor T-cells via tail-vein injection. Donor chimerism in peripheral blood was determined 1-2 months posttransplant and was typically >95%.…”

“…1,2 We have shown that VIP-knockout (KO) mice are resistant to murine cytomegalovirus (mCMV) infection and that mCMV-resistance can be adoptively transferred by syngeneic bone marrow transplantation (BMT). 8 The mechanism of mCMV resistance in VIP-KO mice appears to be through altering the expression of co-stimulatory and coinhibitory molecules on DC and T-cells leading to increased antigen-specific T-cells. 8 We hypothesized that short-term pharmacological inhibition of VIP signaling could improve immune responses to CMV infection, a common opportunistic infection after allogeneic transplantation.…”

“…8 The mechanism of mCMV resistance in VIP-KO mice appears to be through altering the expression of co-stimulatory and coinhibitory molecules on DC and T-cells leading to increased antigen-specific T-cells. 8 We hypothesized that short-term pharmacological inhibition of VIP signaling could improve immune responses to CMV infection, a common opportunistic infection after allogeneic transplantation. 9,10 To test this hypothesis, and the effect of VIP signaling blockade on GVHD, we infected mice with mCMV following transplantation of major histocompatibility complex (MHC)-mismatched VIP-KO BM or treated recipients of wild-type (WT) allografts with a VIP antagonist.…”

A 2.5-Kilobase Deletion Containing a Cluster of Nine MicroRNAs in the Latency-Associated-Transcript Locus of the Pseudorabies Virus Affects the Host Response of Porcine Trigeminal Ganglia during Established Latency

“…VIP acts as an inhibitor in many biological functions. Its absence induces better Th1 polarization and antiviral immunity in mice (61), and VIP knockout mice have enhanced cellular immune responses and increased survival following murine cytomegalovirus infection (62). Various reports indicate CYP2E1 as a gene downregulated by various stimuli, including inflammation (63).…”

Decoding the chemokine network that links leukocytes with decidual cells and the trophoblast during early implantation

“…It binds to G protein coupled receptors VPAC1 and VPAC2 with potent immunomodulatory and trophic effects on adult and embryonic tissues. [27][28][29][30][31][32][33][34][35][36][37] At the maternal-placental interface, VIP localize in first and third trimester placenta in the syncytium and extravillous cytotrophoblast cells. 38 VIP dose-dependently stimulated hCG production from human primary cultured trophoblast cells as well as choriocarcinoma cell line JEG-3.…”